Multimeric Peptide Copolymer Formulations for Targeted Drug Delivery to Treat Nervous System Disorders Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease that leads to progressive muscle wasting, autonomic dysfunction and death within 5 years of diagnosis, and each year >16,000 people are diagnosed. As research has made tremendous strides in understanding the cellular mechanisms that underlie disease progression, pre-clinical research has demonstrated the potential of nerve growth factor (NGF), glial derived and neural derived neurotrophic factor (GDNF and BDNF), and targeted biologics to halt disease progression. However, the clinical translation of therapeutics to treat ALS and other nervous system disorders has lagged due to complications associated with systemic administration or transient blood-brain barrier damage. By using a bacteriophage biopanning strategy to perform an affinity based screen, we aim to exploit a CNS entry pathway similar to rabies virus infection to circumvent the barriers of systemic delivery and target therapeutics to neurons directly. Thus, we propose to identify novel targeting peptides and biologics delivery strategies to treat nervous system diseases. By using a bacteriophage biopanning strategy to perform an affinity based screen, we have recently identified a peptide motif, TAxI, that mediates uptake and delivery of a biologically active protein to the CNS after intramuscular injection. Here, we demonstrate the ability of CNS targeting-peptides to deliver a model drug into the CNS after IP injection. We propose to evaluate how aging and disease progression impacts targeted drug delivery to the CNS with the goal of designing and synthesizing materials for pre-clinical testing in a model of ALS. In this proposal, we build upon TAxI by developing copolymer materials and a human TAxI-peptide for translatable CNS delivery formulations to deliver biologics into the diseased CNS non- invasively.